Vascular responses to platelet activation in normal and atherosclerotic primates in vivo.

Abstract

Platelets release vasoactive substances that may contribute to augmented vasoconstriction. In this study, we examined vascular responses to activation of platelets in vivo by infusion of collagen. Purified bovine collagen was infused into the blood-perfused hind limb of normal and atherosclerotic cynomolgus monkeys. Resistance of the total limb and large arteries was measured at constant flow. In normal monkeys, collagen produced a decrease in total limb resistance, with a modest constrictor response of the large arteries. In atherosclerotic monkeys, collagen produced a transient, small decrease in total limb resistance, with pronounced constriction of large arteries. Indomethacin (5 mg/kg i.v.) and the thromboxane Aj/prostaglandin H 2 receptor antagonist SQ29,548 (2 mg/kg i.v.) virtually abolished the large-artery constrictor response to collagen in atherosclerotic monkeys. The 5-HT 2 -serotonergic receptor antagonist ketanserin (0.6 mg/kg i.v.) had no effect on the vasoconstrictor response. We conclude that 1) large arteries constrict and small vessels dilate in response to collagenmediated activation of platelets in vivo in normal and atherosclerotic monkeys, 2) large-artery constriction in response to activation of platelets is augmented in atherosclerotic monkeys, and 3) the augmented large-artery constriction in atherosclerotic monkeys may be mediated primarily by thromboxane. The findings provide evidence that platelets may contribute to augmented constrictor responses of atherosclerotic arteries. (Arteriosclerosis and Thrombosis 1991;11:1745-1751)

Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.

“…Activated platelets release ADP, which is a vasodilator, and serotonin and thromboxane A 2 , which are vasoconstrictors (29,30). In contrast to atherosclerotic monkeys, which exhibit enhanced vasoconstrictor responses to both collagen and serotonin (13,14), we did not observe augmented vasoconstrictor responses to serotonin in hyperhomocyst(e)inemic monkeys. Similarly, we observed no augmentation of carotid artery contraction in response to the thromboxane A 2 analogue U46619 in monkeys that were fed modified diet.…”

“…Monkeys fed hyperhomocyst(e)inemic diet for 4 wk developed vascular dysfunction that was similar in severity to that seen in monkeys fed atherogenic diet for 18 mo (13,26). We speculate that altered vascular function may contribute to vasospasm, thrombosis, and progression of atherosclerosis in hyperhomocyst(e)inemia.…”

“…At doses used in this study, collagen has no direct vasomotor effects but it is a potent activator of platelets in vivo (13). The venous platelet count decreased by ‫ف‬ 30-40% after collagen infusion on both diets, which suggests that increased collageninduced vasoconstriction in monkeys that were fed modified diet was not caused by increased platelet activation.…”

“…The target iliac and femoral arteries were not instrumented during angiography. Quantitation of arterial lumen diameter was performed using computerized arterial lumen edge detection software (12) as we have described previously (13,14). Velocity of blood flow to the leg was measured using the Doppler transducer at the time of angiography.…”

Plasma Concentration of Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Is Elevated in Monkeys With Hyperhomocyst(e)inemia or Hypercholesterolemia

“…Collagen activates platelet aggregation in vivo, 16 which causes greater reduction of peripheral blood flow when endothelium-mediated inhibition of platelet activation is impaired than when endothelial function is normal. 16 Cineangiograms of the distal descending aorta and the left iliac artery were obtained as described previously. 1 Quantification of arterial lumen diameter was performed by the use of computerized arterial lumen edge detection software as described previously.…”